Explicit spatial analysis of infectious diseases recognizes that pathogenic interactions with hosts occur in specific geographic locations at specific times and that often the nature, direction, intensity, and outcome of an epidemic depends upon the location and timing of the outbreak. Infectious diseases, especially directly transmitted diseases, are intrinsically spatially dependent processes relying on patterns of host and pathogen contact, host and pathogen/vector movements, and mosaics of genetic and environmental heterogeneity. All of these spatial variations potentially influence patterns of disease susceptibility, establishment, and spread. Using spatially explicit computer simulations in conjunction with a 30 year database on rabies occurrence in wild raccoon populations along the eastern seaboard of the US, we have successfully completed (1) demonstrating the consistent and predictable temporal structure of epizootic raccoon rabies at the level of individual counties using simple infectious disease dynamics models at a local spatial scale, (2) the construction of a stochastic spatial simulator over heterogeneous landscapes that can accurately predict the spatial trajectory of rabies spread incorporating the effects of different environmental barriers and long-distance translocation of rabid animals, (3) the development of techniques that allow for comparison of transmission rates at different spatial scales, and (4) developed a simulation technique for measuring the quantitative effects of environmental barriers on directionality of epizootic spread. In this proposal, we harness the power of these modeling methods and analytic techniques to understanding the relationship between spatial ecological dynamics and the phylogeography and evolution of viral-host relationships. We intend to (1) use the spatial-temporal simulator to compute the most likely trajectories of rabies movement across the Eastern US, assign most likely locations of long-distance translocation of rabies, and construct an optimized sampling scheme for virus sampling based on mapped trajectories, (2) coordinate with State laboratories to collect raccoon tissues and rabies virus samples from different spatial locations representing different spatial and temporal domains of the epizootic as determined by the optimized sampling design, (3) determine the phylogeographic structure of the raccoon-associated rabies virus over the enzootic region of the mid-Atlantic and New England States and viral isolates from the southeastern US, (4) establish the co-phylogeographic relationship between rabies viruses and their local raccoon hosts, and (5) determine if geographic variation in virulence exists among isolates of raccoon rabies virus coincident with patterns of phylogeography.